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. 2018 Aug 1;140(30):9652-9658.
doi: 10.1021/jacs.8b05549. Epub 2018 Jul 17.

Concise Synthesis of (-)-Cycloclavine and (-)-5- epi-Cycloclavine via Asymmetric C-C Activation

Lin Deng  1 , Mengqing Chen  1   2 , Guangbin Dong  1
Affiliations

Concise Synthesis of (-)-Cycloclavine and (-)-5- epi-Cycloclavine via Asymmetric C-C Activation

Lin Deng et al. J Am Chem Soc. .

Abstract

To illustrate the synthetic significance of C-C activation methods, here we describe an efficient strategy for the enantioselective total syntheses of (-)-cycloclavine and (-)-5- epi-cycloclavine, which is enabled by an asymmetric Rh-catalyzed "cut-and-sew" transformation between benzocyclobutenones and olefins. Despite the compact structure of cycloclavine with five-fused rings, the total synthesis was accomplished in 10 steps with a 30% overall yield. Key features of the synthesis include (1) a Pd-catalyzed tandem C-N bond coupling/allylic alkylation sequence to construct the nitrogen-tethered benzocyclobutenone, (2) a highly enantioselective Rh-catalyzed carboacylation of alkenes to forge the indoline-fused tricyclic structure, and (3) a diastereoselective cyclopropanation for preparing the tetrasubstituted cyclopropane ring. Notably, an improved catalytic condition has been developed for the nitrogen-tethered cut-and-sew transformation, which uses a low catalyst loading and allows for a broad substrate scope with high enantioselectivity (94-99% e.e.). The C-C activation-based strategy employed here is anticipated to have further implications for syntheses of other natural products that contain complex fused or bridged rings.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
“Cut-and-sew” approach for bridged and fused ring synthesis.
Figure 2.
Figure 2.
Structures of representative ergot alkaloids.
Figure 3.
Figure 3.
X-ray structures of compound 9b (racemic).
Figure 4.
Figure 4.
Stereochemical model for the cyclopropanation step.
Scheme 1.
Scheme 1.
Prior Strategies towards Total Synthesis of Cycloclavine
Scheme 2.
Scheme 2.
Retrosynthetic Analysis for the Synthesis of (−)-Cycloclavine: A C–C Activation Strategy
Scheme 3.
Scheme 3.
Cut-and-Sew Reaction with Nitrogen-Tethered Substrates
Scheme 4.
Scheme 4.
Synthesis of the Nitrogen-Tethered Benzocyclobutenone Substrate
Scheme 5.
Scheme 5.
Synthesis of Compound 3 as the Substrate for Cyclopropanation
Scheme 6.
Scheme 6.
Synthesis of (−)-5-epi-Cycloclavine
Scheme 7.
Scheme 7.
Total Synthesis of (−)-Cycloclavine
Scheme 8.
Scheme 8.
Summary of the Synthetic Route
See this image and copyright information in PMC

References

    1. For selected reviews, see:

    2. Crabtree RH Chem. Rev 1985, 85, 245.
    3. Jones WD Nature 1993, 364, 676.
    4. Murakami M; Ito Y Top. Organomet. Chem 1999, 3, 97.
    5. Rybtchinski B; Milstein D Angew. Chem., Int. Ed 1999, 38, 870. - PubMed
    6. Jun C-H Chem. Soc. Rev 2004, 33, 610. - PubMed
    7. Necas D; Kotora M Curr. Org. Chem 2007, 11, 1566.
    8. Park YJ; Park J-W; Jun C-H Acc. Chem. Res 2008, 41, 222. - PubMed
    9. Murakami M; Matsuda T Chem. Commun 2011, 47, 1100. - PubMed
    10. Seiser T; Saget T; Tran DN; Cramer N Angew. Chem., Int. Ed 2011, 50, 7740. - PubMed
    11. Korotvicka A; Necas D; Kotora M Curr. Org. Chem 2012, 16, 1170.
    12. Chen F; Wang T; Jiao N Chem. Rev 2014, 114, 8613. - PubMed
    13. Dermenci A; Coe JW; Dong G Org. Chem. Front 2014, 1, 567. - PMC - PubMed
    14. Dong G C–C bond activation; Springer-Verlag: Berlin, 2014; Vol. 346.
    15. Murakami M; Ishida N Fundamental Reactions to Cleave Carbon–Carbon σ-Bonds with Transition Metal Complexes. In Cleavage of Carbon–Carbon Single Bonds by Transition Metals; Wiley-VCH Verlag GmbH & Co. KGaA: 2015; pp 1.
    16. Souillart L; Cramer N Chem. Rev 2015, 115, 9410. - PubMed
    17. Chen P.-h.; Dong G Chem. - Eur. J 2016, 22, 18290. - PMC - PubMed
    18. Chen P.-h.; Billett BA; Tsukamoto T; Dong G ACS Catal. 2017, 7, 1340. - PMC - PubMed
    19. Fumagalli G; Stanton S; Bower JF Chem. Rev 2017, 117, 9404. - PubMed
    20. Kim D-S; Park W-J; Jun C-H Chem. Rev 2017, 117, 8977. - PubMed

    1. For selected reviews, see:

    2. Murakami M; Ishida N Total Syntheses of Natural Products and Biologically Active Compounds by Transition-Metal-Catalyzed C–C Cleavage. In Cleavage of Carbon-Carbon Single Bonds by Transition Metals; Wiley-VCH Verlag GmbH & Co. KGaA: 2015; pp 253. For selected examples, see:
    3. South MS; Liebeskind LS J. Am. Chem. Soc 1984, 106, 4181.
    4. Wender PA; Fuji M; Husfeld CO; Love JA Org. Lett 1999, 1, 137.
    5. Trost BM; Waser J; Meyer AJ Am. Chem. Soc 2007, 129, 14556. - PMC - PubMed
    6. Jiao L; Yuan C; Yu Z-XJ Am. Chem. Soc 2008, 130, 4421. - PubMed
    7. Nakao Y; Ebata S; Yada A; Hiyama T; Ikawa M; Ogoshi SJ Am. Chem. Soc 2008, 130, 12874. - PubMed
    8. Hirata Y; Yukawa T; Kashihara N; Nakao Y; Hiyama TJ Am. Chem. Soc 2009, 131, 10964. - PubMed
    9. Liang Y; Jiang X; Yu Z-X Chem. Commun 2011, 47, 6659. - PubMed
    10. Evans PA; Inglesby PA; Kilbride K Org. Lett 2013, 15, 1798. - PubMed
    11. Xu T; Dong G Angew. Chem., Int. Ed 2014, 53, 10733. - PMC - PubMed
    12. Sun T; Zhang Y; Qiu B; Wang Y; Qin Y; Dong G; Xu T Angew. Chem., Int. Ed 2018, 57, 2859. - PubMed
    1. Xu T; Dong G Angew. Chem., Int. Ed 2012, 51, 7567. - PubMed
    1. Souillart L; Parker E; Cramer N Asymmetric Transformations via C–C Bond Cleavage In C–C Bond Activation; Dong G, Ed.; Springer: Berlin Heidelberg, 2014; pp 163. - PubMed
    1. For asymmetric C–C activation reactions via oxidative addition, see:
    2. Xu T; Ko HM; Savage NA; Dong GJ Am. Chem. Soc 2012, 134, 20005. - PubMed
    3. Parker E; Cramer N Organometallics 2014, 33, 780.
    4. Souillart L; Cramer N Angew. Chem., Int. Ed 2014, 53, 9640. - PubMed
    5. Souillart L; Parker E; Cramer N Angew. Chem., Int. Ed 2014, 53, 3001. - PubMed
    6. Zhou X; Dong GJ Am. Chem. Soc 2015, 137, 13715. - PMC - PubMed
    7. Deng L; Xu T; Li H; Dong GJ Am. Chem. Soc 2016, 138, 369. - PMC - PubMed

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